Advances In Systemic Therapy Research Articles

Abstract P1-21-02: Scalp sparing whole-brain radiotherapy using IMRT technique. Do we need it?

Abstract Introduction: The prognosis of metastatic breast cancer patients is improving due to advances in systemic therapy, which led to better control of the disease. Brain metastasis that requires whole-brain radiotherapy (WBRT) is mandatory for some patients.Acute alopecia is a common side effect, and total hair loss occurs in 100% of patients receiving parallel opposed direct laterals fields.Because of the recognized reduction in quality of life associated with clinically apparent and clinically undetectable hair loss, efforts are made to minimize hair loss resulting from WBRT.It is theorized that intensity-modulated radiotherapy (IMRT) may reduce hair loss. It will be less patchy because IMRT enables dose modulation, minimizing the radiation dose received by the hair follicles in the scalp.This dosimetric study assessed the dose received to the whole scalp and its subvolumes by three radiotherapy techniques. Methods: A total of 30 treatment plans for ten patients receiving WBRT were evaluated retrospectively. All patients were simulated in a supine position with a thermoplastic mask. The scalp was contoured as 5 mm between the skin and the outer table of the skull. Then we subdivided the scalp volume into superior, anterior, lateral, and posterior subvolumes. The dose prescribed was 30 Gy in 10 fractions. We compared three different radiotherapy techniques using the standard WBRT procedure that involves applying two lateral opposing fields (OF-WBRT) with a margin surrounding the brain, which includes the hair follicles situated about 5 mm. below the scalp, the field in field (FiF), and IMRT techniques without introducing the scalp in the optimization process using 6 MV photon energy. Results: All techniques showed comparable PTV coverage. The homogeneity index with opposed lateral was 0.057±.09, 0.057±.0111 for FiF, and 058±.0114 for IMRT with no statistically significant difference (p = 0.407).IMRT resulted in a marked decrease in all scalp parameters with a statistically significant difference, with a little difference in the dose delivered to lateral subvolumes. (table 1) Conclusion: Scalp sparing IMRT for WBRT reduces the scalp dose compared to conventional WBRT, especially in the superior, anterior and posterior axis. Further randomized prospective trials are needed to confirm this benefit. 2 Table. PTV coverage and dose to the scalp and its subvolumes.characteristicsOPPOSED LATERALFIFIMRTP-ValueMean ± SDMean ± SDMean ± SDAll groupsOpposes lateral/FIFOpposes lateral/IMRTIMRT/FIFPTV D 98%96.9±0.796.9±0.797.1±0.71.000Scalp mean dose (cGy)2165.7±270.52120.5±242.81385.9±306.7<0.0010.076<0.0010.076Scalp V 20 (%)68.4±12.567.1±11.237.6±11.2<0.0010.221<0.0010.042Superior mean dose (cGy)2396.8±138.92326.1±1211419.0± 372.4<0.0010.076<0.0010.076Anterior mean dose (cGy)2180.9±237.82209.7±205.01267.4±462.2<0.0010.221<0.0010.042Lateral mean dose (cGy)2127.7±252.62136.9±249.12071.4±257.10.0020.2210.2210.001Posterior meanDose (cGy)2317.8±205.62273.3±207.81467.2±209.7<0.0010.0760.076<0.001 Citation Format: Mohsen Samy Barsoum, Emad Mohsen Barsoum, Maha Kamaleldin, Niven Mahmoud, Shaimaa Abdelgeleel, May Gamal Ashour. Scalp sparing whole-brain radiotherapy using IMRT technique. Do we need it? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-02.

Image-Guided Robotic Radiosurgery for the Treatment of Lung Metastases of Renal Cell Carcinoma-A Retrospective, Single Center Analysis.

Simple SummaryPatients with metastatic renal cell carcinoma are difficult to treat despite many new systemic therapy options. Patients often present with pulmonary metastases. Local treatment of those metastases is traditionally performed surgically. In this study, robotic radiosurgery is tested in 50 patients with pulmonary metastases and is demonstrated to be a safe and highly effective treatment option in this patient group. Future research might focus on the combination of robotic radiosurgery with systemic treatment.Pulmonary metastases are the most frequent site of metastases in renal cell carcinoma (RCC). Metastases directed treatment remains an important treatment option despite advances in systemic therapies. However, the safety and efficacy of robotic radiosurgery (RRS) for the treatment of lung metastases of RCC remains unclear. Patients with metastatic RCC and lung metastases treated by RRS were retrospectively analyzed for overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS) and adverse events. The Kaplan–Meier method was used for survival analysis and the common terminology criteria for adverse events (CTCAE; Version 5.0) classification for assessment of adverse events. A total of 50 patients were included in this study. Median age was 64 (range 45–92) years at the time of RRS. Prior to RRS, 20 patients (40.0%) had received either tyrosine kinase inhibitors or immunotherapy and 27 patients (54.0%) were treatment naïve. In our patient cohort, the median PFS was 13 months (range: 2–93). LRFS was 96.7% after two years with only one patient revealing progressive disease of the treated metastases 13 months after RRS. Median OS was 35 months (range 2–94). Adverse events were documented in six patients (12%) and were limited to grade 2. Fatigue (n = 4) and pneumonitis (n = 2) were observed within 3 months after RRS. In conclusion, RRS is safe and effective for patients with metastatic RCC and pulmonary metastases. Radiation induced pneumonitis is specific in the treatment of pulmonary lesions, but not clinically relevant and survival rates seem favorable in this highly selected patient cohort. Future directions are the implementation of RRS in multimodal treatment approaches for oligometastatic or oligoprogressive disease.

Survival of patients with stage IIIC and IIID melanomas with nodal metastases in the light of new therapies.

Within stage III melanoma prognosis and outcomes significantly vary. Advances in systemic therapy improved prognosis in metastatic melanoma. Adjuvant therapy in stage III significantly lowered relapses, although the effect on survival is less evident. Analysis of treatment results in stage IIIC and IIID before introduction of the modern adjuvant therapy, but after introduction of the effective systemic therapy in metastatic relapse, is needed. To analyse the clinical outcomes in patients with stage IIIC and IIID melanoma before the introduction of the novel adjuvant therapy. Consecutive stage IIIC and IIID melanoma patients treated in 2015-2018 in 4 reference centres in Poland were enrolled in the analysis of RFS and OS (in-transit metastases excluded). Median follow-up was 26.6 months (1.7-67.2). There were 224 stage IIIC and 49 stage IIID patients. Recurrence was observed in 170 (62.2%); 102 (45.5%) deaths in stage IIIC and 28 (57.1%) in stage IIID were reported. RFS and OS were better in stage IIIC compared to stage IIID. RFS and OS in the IIIC group were 19.7 and 36.2 months, respectively, and in IIID - 8.9 and 27.8 months, respectively. The survival of patients with high-risk melanomas has improved in recent years, however, it is still unsatisfactory. The major changes in melanoma management related to the introduction of the adjuvant therapy require further careful observation.

Management of Cerebral Metastases—About 25 Cases

Approximately, 20% of all cancer patients will end up having brain metastases. This is especially the case of patients in which the primary tumor is lung cancer, breast and colorectal cancers, melanoma, or renal cell carcinoma. Development of brain metastases contributes substantially to overall cancer mortality in patients with advanced-stage cancer given the associated poor prognosis despite multimodal treatments and advances in systemic therapies. The objective of this retrospective single center study is to describe the experience of the Department of Neurosurgery of the Ibn Sina University Hospital in Rabat in the management of patients with brain metastases, highlighting the therapeutic choices as well as the various challenges encountered during treatment.

Recent Advances in Systemic Therapy for HCC

Recent Advances in Systemic Therapy for HCC

Contemporary surgical management of inflammatory breast cancer: a narrative review.

The purpose of this review is to outline the surgical management of inflammatory breast cancer (IBC) including the clinical decision making, operative approach and current controversies. IBC is a rare and aggressive form of breast cancer. Trimodality therapy consisting of neoadjuvant therapy, modified radical mastectomy (MRM) and radiation therapy improves survival and is the recommended course of treatment. Advancements in systemic therapy and de-escalation strategies in non-IBC have accelerated discussions regarding several aspects of care in IBC including feasibility of de-escalation of surgical care, timing of reconstruction and the role of surgery in de novo stage IV disease. We discuss the evidence to support the surgical approach and decision-making in this rare disease. We reviewed existing literature using multiple electronic databases and clinical consensus guidelines to identify historical and current publications addressing current management recommendations and clinical controversies in IBC. Breast conserving surgery (BCS), skin- or nipple-sparing mastectomy should not be performed in IBC as surgical resection to negative margins results in improved locoregional recurrence rates. Level I and II axillary lymph node dissection should be performed regardless of response to therapy and initial nodal status. Reconstruction should be delayed and contralateral prophylactic mastectomy (CPM) is discouraged in IBC. Surgery may be considered for de novo stage IV IBC patients who demonstrate durable response to neoadjuvant therapy to improve local-regional control.

Abstract P012: Genomic and clinical correlates of overall survival (OS) in men with newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT)

Abstract Background: Despite recent advancements in systemic therapy in men with mCSPC, disease remains fatal. Identification of novel genomic and clinical correlates of survival in this setting remain a significant unmet need. Methods: Newly diagnosed mCSPC undergoing intensified ADT i.e., ADT plus docetaxel or novel hormonal therapy and available tumor comprehensive genomic profiling (CGP) were included in the analysis. CGP was performed by a CLIA certified Next Generation Sequencing panel (Foundation Medicine) and involved the following genes: FAS, KDM6A, MYC1, PTEN, RB1, TMPRSS2, and TP53. All variants of unknown significance were removed, and mutated genes present in ≥5 % patients were included. Cox proportional hazards was used to assess relationships between OS and multiple variables (age at diagnosis, Gleason score, baseline PSA, de-novo disease, volume of disease, presence of visceral metastases and presence of genetic aberrations on CGP). Results: 127 patients were eligible and included. Higher baseline PSA (HR 1.45, 95% CI 1.09-1.9, P=0.0097), presence of visceral metastases (HR 4.41, 95% CI 1.26-15.39, P=0.0199) and genomic aberrations in MYC1 (HR 5.23, 95% CI 1.05-26.04, P=0.0433) and RB1 (HR 32.72, 95% CI 5.35-200.2, P=0.0002) were significantly associated with inferior OS. High volume disease trended to associate with poor OS, but was not statistically significant (HR 1.63, 95% CI 0.56-4.71, P=0.367). PTEN loss and other genomic aberrations were not associated with OS. See Table. Conclusions: In this real-world patient population of men with mCSPC undergoing intensified ADT we identify clinical and genomic markers associated with poor OS. This study has limitations as expected in a retrospective analysis. These data, upon external validation, may aid with development of a risk stratification model, counseling of patients, treatment decision making in the clinic, as well as further drug development. Citation Format: Nicolas Sayegh, Bennet Peterson, Roberto Nussenzveig, Adam Kessel, Taylor Ryan McFarland, Andrew Warren Hahn, Deepika Sirohi, Manish Kohli, Benjamin Louis Maughan, Umang Swami, Mark Yandell, Neeraj Agarwal. Genomic and clinical correlates of overall survival (OS) in men with newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P012.

Stereotactic body radiation therapy for primary liver tumors: An effective liver-directed therapy in the toolbox.

The use of radiation for primary liver cancers has historically been limited because of the risk of radiation-induced liver disease. Treatment fields have become more conformal because of several technical advances, and this has allowed for dose escalation. Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy, is now able to safely treat liver tumors to ablative doses while sparing functional liver parenchyma by using highly conformal therapy. Several retrospective and small prospective studies have examined the use of SBRT for liver cancers; however, there is a lack of well-powered randomized studies to definitively guide management in these settings. Recent advances in systemic therapy for primary liver cancers have improved outcomes; however, the optimal selection criteria for SBRT as a local therapy remain unclear among other liver-directed options such as radiofrequency ablation, transarterial chemoembolization, and radioembolization.

Contemporary Outcomes After Multimodality Therapy in Patients With Breast Cancer Presenting With Ipsilateral Supraclavicular Node Involvement

PurposePatients with breast cancer and ipsilateral supraclavicular (SCV) node involvement at the time of diagnosis (TNM cN3c) have historically had poor outcomes. Radiation therapy (RT) has an important role because SCV nodes are not routinely surgically dissected. However, optimal locoregional management, contemporary outcomes, and prognostic factors are not well defined. Methods and MaterialsWe reviewed the data of patients with cN3c breast cancer treated at our institution between 2014 and 2019 with curative intent, including neoadjuvant chemotherapy, surgery, and adjuvant RT. All patients received comprehensive regional RT, including to the SCV nodes. Institutional guidelines recommend a 10-Gy or 16-Gy boost to resolved and unresolved N3 nodes, respectively. Overall survival (OS), recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and supraclavicular recurrence-free survival (SCRFS) were analyzed. ResultsData from 173 consecutive patients were analyzed with a median follow-up time of 2.8 years. The median age was 54 years, 76 patients (44%) were estrogen receptor positive/human epidermal growth factor receptor 2 negative, 100 patients (58%) had T3/4 disease, and 10 patients (6%) underwent a neck dissection. In addition, 156 patients (90%) received a cumulative SCV dose of ≥60 Gy. The 5-year OS, SCRFS, LRRFS, and RFS rates were 73%, 95%, 86%, and 50%, respectively. The 5-year OS rate for a cumulative SCV dose of ≥60 Gy versus <60 Gy was 75% versus 39% (P = .04). In the multivariable analysis, a cumulative SCV dose of ≥60 Gy, extranodal extension, receptor status, and Eastern Cooperative Oncology Group performance status were associated with OS. The 5-year SCRFS rates with and without neck dissection were 100% versus 95% (P = .57). Among patients with a postchemotherapy SCV node size of ≥1 cm without neck dissection, the 5-year SCRFS rate was 83%. ConclusionsIn one of the largest series of patients with cN3c breast cancer, multimodality therapy using adjuvant RT with a SCV boost resulted in a 5-year LRRFS rate of 86%. There is a limited role for neck dissection as the 5-year SCRFS rate was 95% overall and 83% for residual SCV disease ≥1 cm after chemotherapy with RT alone. A cumulative SCV dose of ≥60 Gy was associated with improved OS, but not SCRFS, LRRFS, or RFS. A SCV boost should be considered in these patients as treatment was well-tolerated. Despite advances in systemic therapy, nearly half of patients developed distant metastases, highlighting the need for close observation after treatment.

Survival in Patients with ≥5 Brain Metastases From Non-Small Cell Lung Cancer Treated With Upfront Stereotactic Radiosurgery

Multiple brain metastases (BM) from non-small cell lung cancer (NSCLC) historically has a dismal prognosis. Advances in systemic therapy for NSCLC have significantly improved survival, but the effect on prognosis in patients with NSCLC and BM is poorly understood. Stereotactic radiosurgery (SRS) may result in local control even with higher numbers of BM. We report survival outcomes of upfront SRS for ≥5 BM from metastatic NSCLC.Review of our registry identified 177 patients treated for ≥5 BM from NSCLC between 2012 and 2020, and did not undergo prior intracranial radiation or resection.Adenocarcinoma was found in 129 patients (73%). EGFR/ALK mutations were identified in 54 patients (31%). The median number of tumors at initial SRS were 8 (range 5-35). 121 patients (68%) were treated for 5-10 BM, 31 patients (18%) for 11-15 BM, and 25 patients (14%) for > 15 BM. The median overall survival (OS) from initial SRS for all patients was 15.1 months (95% CI 11.5-18.7). Survival at 1, 2, and 3 years was 57%, 39%, and 28% respectively. Adenocarcinoma was associated with improved survival compared to non-adenocarcinoma (P < 0.001), median OS 17.1 months (95% CI 11.4-22.9) and median OS 5.7 months (95% CI 2.8-8.6), respectively. Patients with EGFR/ALK mutations had a significantly greater survival time compared to those without (P = 0.008), and median OS of 26.3 months (95% CI 19.1-33.6) versus 10.4 months (95% 6.2-14.6). Treatment of 5-10, 11-15, or > 15 tumors at initial GK were not associated with differences in survival (P = 0.48). On multivariate analysis, survival benefit remained significant in patients with adenocarcinoma (HR 0.42, 95% CI 0.24-0.72, P = 0.002), and patients with EGFR/ALK mutations (HR 0.58, 95% CI 0.37-0.91, P = 0.02).Patients treated with initial SRS for multiple BM from NSCLC in the modern era demonstrate longer survival as compared with historical reports. Adenocarcinoma subtype, particularly in the setting of EGFR/ALK mutation is associated with improved prognosis, even in patients with higher number of metastases.J. Gurewitz: None. D. Patel: None. C. Benjamin: None. B.R. Donahue: None. J. Silverman: None. M. Mureb: None. K. Bernstein: None. D. Kondziolka: None.

Neoadjuvant chemotherapy for colorectal liver metastases: A contemporary review of the literature.

Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide, and up to 50% of patients with CRC develop colorectal liver metastases (CRLM). For these patients, surgical resection remains the only opportunity for cure and long-term survival. Over the past few decades, outcomes of patients with metastatic CRC have improved significantly due to advances in systemic therapy, as well as improvements in operative technique and perioperative care. Chemotherapy in the modern era of oxaliplatin- and irinotecan-containing regimens has been augmented by the introduction of targeted biologics and immunotherapeutic agents. The increasing efficacy of contemporary systemic therapies has led to an expansion in the proportion of patients eligible for curative-intent surgery. Consequently, the use of neoadjuvant strategies is becoming progressively more established. For patients with CRLM, the primary advantage of neoadjuvant chemotherapy (NCT) is the potential to down-stage metastatic disease in order to facilitate hepatic resection. On the other hand, the routine use of NCT for patients with resectable metastases remains controversial, especially given the potential risk of inducing chemotherapy-associated liver injury prior to hepatectomy. Current guidelines recommend upfront surgery in patients with initially resectable disease and low operative risk, reserving NCT for patients with borderline resectable or unresectable disease and high operative risk. Patients undergoing NCT require close monitoring for tumor response and conversion of CRLM to resectability. In light of the growing number of treatment options available to patients with metastatic CRC, it is generally agreed that these patients are best served at tertiary centers with an expert multidisciplinary team.

Debulking surgery for malignant tumors: the current status, evidence and future perspectives.

Debulking surgery, also called cytoreductive surgery, is a resection of the tumor as much as possible and an intended incomplete resection for unresectable malignant tumors. Since the most important principle in surgical oncology is complete R0 resection, debulking surgery goes against the basic principle and obscures the concept of operability. However, debulking surgery has been advocated for various types of advanced malignant tumors, including gynecological cancers, urological cancers, gastrointestinal cancers, breast cancers and other malignancies, with or without adjuvant therapy. Positive data from randomized trials have been shown in subsets of ovarian cancer, renal cell carcinoma, colorectal cancer and breast cancer. However, recent trials for renal cell carcinoma, colorectal cancer and breast cancer have tended to show controversial results, mainly according to the survival improvement of nonsurgical systemic therapy alone. On the other hand, debulking surgery still has a therapeutic role for slow-growing and borderline malignant tumors, such as pseudomyxoma peritonei and thymomas. The recent understanding of tumor heterogeneity and clonal evolution responsible for malignancy and drug resistance indicates that select patients may obtain prolonged survival by the synergistic effect of debulking surgery and novel systemic therapy. This review aimed to describe the current status and evidence of debulking surgery in a cross-organ manner and to discuss future perspectives in the current era with advances in systemic therapy.

Systemic treatment of hepatocellular carcinoma: An EASL position paper

The last 5 years have witnessed relevant advances in the systemic treatment of hepatocellular carcinoma. New data have emerged since the development of the EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma in 2018. Drugs licensed in some countries now include 4 oral multi-tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib), 1 anti-angiogenic antibody (ramucirumab) and 4 immune checkpoint inhibitors, alone or in combination (atezolizumab in combination with bevacizumab, ipilimumab in combination with nivolumab, nivolumab and pembrolizumab in monotherapy). Prolonged survival in excess of 2 years can be expected in most patients with sensitive tumours and well-preserved liver function that renders them fit for sequential therapies. With different choices available in any given setting, the robustness of the evidence of efficacy and a correct matching of the safety profile of a given agent with patient characteristics and preferences are key in making sound therapeutic decisions. The recommendations in this document amend the previous EASL Clinical Practice Guidelines and aim to help clinicians provide the best possible care for patients today. In view of several ongoing and promising trials, further advances in systemic therapy of hepatocellular carcinoma are foreseen in the near future and these recommendations will have to be updated regularly.

Evolution of systemic treatment for advanced hepatocellular carcinoma.

Advanced hepatocellular carcinoma (HCC) was considered an inherently refractory tumor in the chemotherapy era (1950-2000). However, systemic therapy has evolved to molecular targeted therapy and immunotherapy, and nine treatment regimens have been approved worldwide during the past 20 years. The approved regimens target tumor angiogenesis or tumor immunity, the two cancer hallmarks. Recently, the combination of atezolizumab (antiprogrammed cell death ligand 1) and bevacizumab (anti-vascular endothelial growth factor) has improved the efficacy of systemic therapy in treating advanced HCC without excessive toxicities or deterioration of quality of life. This review summarizes the major advances in systemic therapy and provides future perspectives on the next-generation systemic therapy for advanced HCC.

The role of the surgeon in the management of oligometastatic non-small cell lung cancer: a literature review.

ObjectiveIn this review, we aim to summarize the most recent data on the surgical management of oligometastatic non-small cell lung cancer (NSCLC).BackgroundApproximately 60–70% of all patients with NSCLC initially present with advanced stages of cancer at time of diagnosis. These patients are generally treated with chemotherapy, radiation therapy, or a combination of these modalities. Patients with late-stage disease are usually not considered to be amenable for curative-intent treatments due to poor prognoses. Despite advances in systemic therapies, 5-year overall survival rates in these patients remain poor. However, technological advances in imaging modalities and new imaging strategies have substantially increased tumor detection rates and have resulted in a shift towards earlier diagnosis of NSCLC, possibly in stages in which metastatic disease is limited and still treatable. Studies in recent years have shown that there is a distinct group of patients with metastatic lesions at one or a few sites, often referred to as oligometastatic disease, that may have better survival outcomes compared to patients with more disseminated diseases. Furthermore, it is suggested that these patients may benefit from a combination of systemic treatment and local treatment aimed at the metastatic site(s). However, the role of surgery in this setting remains a controversial subject, with many unanswered questions.MethodsThe PubMed/MEDLINE database and the Cochrane database were searched to find relevant articles regarding oligometastatic NSCLC. Specifically, articles regarding definitions of oligometastatic disease, oligometastatic tumor biology, diagnosis, and the treatment of oligometastatic disease were identified.ConclusionsOligometastatic NSCLC represents a wide spectrum of diseases and encompasses a heterogeneous patient population. Current data suggests that local ablative treatment of oligometastatic lesions with surgery or stereotactic body radiation therapy may result in improved overall survival and progression-free survival rates. However, more data from multi-center prospective trials are necessary to shed light on which therapeutic modalities are most suitable for the treatment of oligometastatic NSCLC. Integration of clinical and molecular staging data is necessary to allow for more personalized treatment approaches.

Biomarkers in cutaneous melanoma: castles in the sky and useful developments

Recent advances in systemic therapy have improved outcomes for patients with advanced stage cutaneous melanoma. This has led to an increased clinical need for biomarkers to identify patients with early stage disease who are likely to benefit from adjuvant treatment. Prognostic calculators can refine prediction of the risk of recurrence by incorporating additional clinicopathological parameters that are not included in melanoma staging by the 8th edition of the AJCC Cancer Staging Manual. Novel prognostic biomarkers are being developed through a range of molecular methods, including gene expression profiling, targeted sequencing and proteomics. There is also a need for improved predictive biomarkers, to identify patients whose melanomas will respond to immunotherapy and distinguish those who are at risk of toxicity without therapeutic benefit. This presentation provides a snapshot of recent developments and future challenges in the development and application of biomarkers in the management of primary cutaneous melanoma.

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review.

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

Survival trends of men and women with metastatic clear cell renal cell carcinoma.

4566 Background: Clear cell renal cell carcinoma (ccRCC) is nearly twice as common in men as in women, and women with non-metastatic RCC have a better prognosis than men. The etiology for these disparities is not known, though sex-specific differences in risk factor prevalence and tumor biology have been reported. The differential impact of systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), on prognosis in women and men with metastatic ccRCC is not defined. Methods: Clinicopathologic features and survival of patients with clinical stage IV ccRCC were obtained from the National Cancer Database (NCDB). Patients were grouped by date of metastatic diagnosis into three eras that correspond to major advances in systemic therapy: 2004-2005 (pre-TKI), 2006-2014 (TKI), and 2015-2016 (ICI). Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: 15,025 male and 7,100 female patients with metastatic ccRCC were identified. Demographic features were similar between cohorts though females were slightly older (median 64.8 vs 62.7 mo, p &lt; 0.0001), more likely to be black (6.5% vs 6.0%, p = 0.0119) or receiving Medicare benefits (46.4% vs 39.9%, p &lt; 0.0001). In the combined cohort, median overall survival (OS) was higher in patients diagnosed in the ICI vs TKI (23.0 vs 16.5 mo) and pre-TKI eras (14.4 mo, log-rank p &lt; 0.0001). Compared with men of the same age groups, OS was inferior for women age 50-64 yr (median 18.4 vs 21.1mo, p = 0.0084) and &gt; 64 yr (15.3 vs 12.6mo, p = 0.0001), but not &lt; 50 yr (20.3 vs 21.7mo, p = 0.6290). In the ICI era, median OS improved by a lesser absolute but similar relative amount for women compared to men (+5.6mo [+39%] and +7.2mo [+41%]), respectively). After controlling for age, race, Charlson-Deyo score, initial treatment modality, and insurance and socioeconomic status, women remained at increased risk of death in both the ICI era (HR 1.12 [95% CI 1.04-1.22], p = 0.004) and the TKI era (HR 1.08 [1.04-1.12], p &lt; 0.001). Conclusions: Women with metastatic ccRCC have a worse prognosis than men which is not explained by demographic differences. This disparity is observed in both the TKI and ICI eras. This finding contrasts with previous studies suggesting women with localized RCC have a favorable prognosis compared with men. Further investigation into the sex-specific biology of metastatic ccRCC is warranted.

Recurrent disease in patients with stage III melanoma in the era of adjuvant immune and targeted therapy.

e21570 Background: Advancements in systemic therapy have reduced recurrence, and the adoption of nodal surveillance in place of dissection has reduced morbidity for patients with Stage III melanoma. The objective of this study was to describe the timing and pattern of recurrence in stage III melanoma patients and evaluate the impact of adjuvant treatment and nodal surveillance. Methods: A multicenter retrospective chart review of patients with pathologically confirmed Stage III cutaneous melanoma seen at either the Juravinski Cancer Centre or Walker Family Cancer Centre in Ontario, Canada from January 1, 2017 to December 31, 2019. Results: There were 137 patients with Stage III melanoma: 18% IIIA, 22% IIIB, 52% IIIC, and 8% Stage IIID as per the 8th American Joint Committee on Cancer (AJCC) 2018 staging system. 103 (75%) patients had sentinel lymph node biopsy (SLNB) only as part of initial surgical therapy, 6 (4%) had SLNB with completion dissection, and 25 (18%) had upfront radical nodal dissection. 67 (49%) patients received adjuvant therapy, of which 50 (74%) had immunotherapy, 17 (25%) received BRAF-targeted therapy, and 1 (1%) had interferon. 54 (39%) patients developed recurrent disease, with a median time to recurrence of 8.5 months (IQR: 4.3-14.9). The recurrence rates were 63% in patients who did not have adjuvant treatment and 37% in those who had adjuvant therapy, with a median time-to-recurrence of 7.5 and 9.0 months respectively. There were 30 (56%) loco-regional recurrences and 24 (44%) distant recurrences. Of the patients with loco-regional recurrence, 26 (87%) had SLNB only compared to 4 (13%) who had upfront or completion dissection. 12 (24%) patients recurred while on adjuvant treatment (7 distant recurrences and 5 loco-regional recurrences), and 8 (13%) patients recurred following completion of adjuvant treatment (5 distant recurrences and 3 loco-regional recurrences). Recurrences were detected by patients, clinicians, CT and nodal US surveillance in 43%, 20%, 28% and 9% of cases, respectively. The majority of loco-regional recurrence was detected clinically (67%) rather than by radiologic surveillance (33%). Of the 30 loco-regional recurrences, 24 underwent surgical resection of the recurrence, 4 had subsequent systemic therapy without surgery, 1 had intra-tumoral injections and 1 had no treatment. Conclusions: Recurrences in Stage III melanoma occur early, often within a year, with higher rates of loco-regional rather than distant disease. Recurrence rates were lower in those who received adjuvant therapy, but the majority of recurrences were detected by patients or clinicians, including loco-regional recurrences in patients who had SLNB only despite surveillance nodal US.

Limited brain metastases: a narrative review.

Limited brain metastases refer to an oligometastatic state in the brain for which focal therapy with stereotactic radiosurgery (SRS) is appropriate. The definition of what is considered "limited" for brain metastases, however, is not well defined. Multiple recent randomized trials show that metastasis-directed therapy with surgery or stereotactic radiation can prolong survival for patients with 1-5 metastases from various primary tumors, but patients with untreated brain metastases were largely excluded from these trials. Stereotactic radiosurgery allows for the treatment of multiple brain metastases while avoiding whole brain radiation (WBRT), which has a known negative impact on neurocognitive function. Randomized trials have shown that stereotactic radiation alone is effective for the treatment of up to 4 brain metastases with decreased neurocognitive side effects and no detriment to overall survival (OS). These data have led to our current definition of "limited" brain metastases. However, more recent data suggests that patients with up to 10 brain metastases can benefit from SRS. Ongoing trials are investigating if patients with up to 15-20 brain metastases may similarly benefit from SRS alone. Advances in systemic therapies which penetrate the blood-brain barrier and have greater activity in central nervous system (CNS) may also expand the population for whom radiosurgery is an appropriate treatment. Immunotherapy may also be synergistic with radiosurgery in some cases. This narrative review will discuss the evolving definition and management of limited brain metastases.